Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease
Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease
复制标题
线粒体三功能蛋白α亚基的乙酰化增强其稳定性，促进脂肪酸氧化，并在非酒精性脂肪肝病中减少
DOI：
10.1128/mcb.00227-16
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发表时间：
2016-10-15
影响因子：
5.3
通讯作者：
Tang, Qi-Qun
中科院分区：
文献类型：
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作者：
Guo, Liang;Zhou, Shui-Rong;Tang, Qi-Qun
非酒精性脂肪性肝病（NAFLD）已成为最常见的肝脏疾病，而脂肪酸氧化降低是NAFLD的重要诱因之一。线粒体三功能蛋白α -亚基（MTP α）是脂肪酸β -氧化的关键酶，但MTP α的失调是否与NAFLD有致病关系尚不清楚。我们发现MTP α在赖氨酸残基350、383和406 （MTP α - 3k）处被乙酰化，这通过拮抗其在相同的三个赖氨酸（MTP α - 3k）上的泛素化并阻断其随后的降解来促进其蛋白质稳定性。Sirtuin 4 （SIRT4）已被确定为去乙酰化酶，使MTP α去乙酰化和不稳定。用MTP α - 3kr或MTP α - 3kq替代MTP α - 3k抑制游离脂肪酸（FFA）处理的α小鼠肝12 （AML12）细胞和原代肝细胞以及高脂/高糖（HF/HS）饮食喂养的小鼠肝脏中的细胞脂质积累。此外，敲低SIRT4可以表型化小鼠肝脏中MTP α - 3k突变体表达的影响，并且MTP α - 3k突变体更有效地减弱HF/HS饮食喂养小鼠中SIRT4介导的肝脏脂肪变性。重要的是，在患有NAFLD的小鼠和人的肝脏中，MTP α和MTP α - 3k的乙酰化降低，而SIRT4升高。我们的研究揭示了MTP α通过乙酰化和泛素化调控的新机制，以及这种调控与NAFLD的直接功能联系。
Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein alpha-ubunit (MTP alpha ) functions as a critical enzyme for fatty acid beta-oxidation, but whether dysregulation of MTP alpha is pathogenically connected to NAFLD is poorly understood. We show that MTP alpha is acetylated at lysine residues 350, 383, and 406 (MTP alpha-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTP alpha-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTP alpha. Replacement of MTP alpha-3K with either MTP alpha-3KR or MTP alpha-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTP alpha-3K mutant expression in mouse livers, and MTP alpha-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTP alpha and MTP alpha-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTP alpha regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD.